The safety, plasma pharmacokinetics, and antiviral activity of T-20 were assessed in a randomized, multicenter, open-label phase 2 clinical trial. T-20 is a 36-amino acid peptide that blocks de novo infection and cell-to-cell virus transmission by inhibiting gp41-mediated fusion. 78 patients with plasma HIV RNA values >5,000 copies/ml on a background of either stable or no ARV therapy were assigned to 6 groups representing T-20 doses ranging from 12.5 to 200 mg/day. T-20 was given by continuous subcutaneous infusion or by b.i.d. subcutaneous injection for 28 days. At entry, mean plasma HIV-RNA was 5.0 log10 copies/ml and mean CD4+ count was 117 cells/mm3. 77 of 78 patients reported antiretroviral experience (mean number of prior ARV's=9) and 98% were protease inhibitor experienced (mean number of prior PI's=3). T-20 was well tolerated at all doses throughout the 28-day treatment period. No treatment-related Grade 3 or 4 systemic toxicities were observed. Two patients withdrew due to AE's. Induration and erythema at the site of infusion or injection were seen in most patients. Sustained steady-state plasma concentrations of T-20 (peak-to-trough ratio <2) were observed both for administration by continuous infusion and by twice-daily injection. A dose-related suppression of plasma HIV RNA was observed. The average maximum change from baseline ranged from -0.3 to 1.6 log10 copies/mL across the treatment groups. The magnitude and durability of viral load suppression was greated in patients with baseline viral load <100,000 copies/mL. T-20 represents the first member of a safe and potent new class of antiretroviral agents that inhibit the function of gp41. Further studies to assess the long-term safety and durability of T-20 in combination therapy are in progress.